Current Opinion in Hematology最新文献

Purpose of review: Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematological malignancies characterized by complex genetic alterations, leading to poor clinical outcomes. Despite advances in treatment, there is an urgent need for novel therapeutic approaches. This review outlines recent progress in humanized models of MDS and AML and highlight their role in advancing our understanding of these diseases.

Recent findings: Patient derived xenografts (PDXs) were among the first humanized models for studying MDS and AML, allowing researchers to analyze patient-specific cancer properties in vivo . However, they face challenges related to sample availability and consistent engraftment in mice. New methods, including specialized mouse strains and human tissue scaffolds, have been developed to address these issues. Induced pluripotent stem cells (iPSCs) offer the advantage of indefinite expansion and genetic modification, making them valuable for in vitro research, though protocols to enhance their engraftment in vivo are still being refined. Genetically engineered human primary hematopoietic stem and progenitor cells (HSPCs) provide reliable in vivo models with good engraftment in mice, and recent advancements in culture systems and gene-editing techniques are helping to overcome challenges related to ex vivo expansion and genetic modification.

Summary: PDXs, iPSCs, and genetically engineered HSPCs are crucial models for the study of MDS and AML. This review discusses strengths, limitations, and recent advancements of these humanized models, which provide insights into human-specific disease biology and therapeutic development.

Purpose of review: To date, there is relatively limited research investigating changes in red blood cells (RBCs), particularly qualitative changes, in cancer patients and cancer patients receiving treatment. These changes may be important in better understanding cancer-associated anemia, which is the most prevalent hematological disorder in cancer patients with wide-ranging implications on patient care and quality of life. This review aims to summarize available evidence regarding qualitative and quantitative changes in RBCs in individuals with cancer prior to treatment and in patients undergoing treatment.

Recent findings: The most commonly reported changes in RBCs in cancer patients were increased mean corpuscular volume (MCV) and decreased hemoglobin, RBC count, and hematocrit. There were increased lipid peroxidation products and decreased antioxidants. There were increased polyunsaturated fatty acids (PUFAs) and decreased monounsaturated fatty acids (MUFAs) and saturated fatty acids (FAs). Additionally, RBC shape alterations with various atypical morphologies, membrane structure abnormalities, and impaired fluidity were also reported. These and various other reported findings are discussed in depth.

Summary: There are several reported quantitative and qualitative RBC changes in individuals with cancer, with some studies exhibiting conflicting results. Further research is needed to solidify the data and to better understand hematological-associated comorbidities in those patients.

Purpose of review: The purpose of this review is to outline current graft versus host disease (GvHD) prophylaxis, in the era of posttransplant cyclophosphamide (PTCY), in patients with malignant and nonmalignant hematologic disorders. The original combination of PTCY with a calcineurin inhibitor (CNI) and mycophenolate (MMF), reported from the Johns Hopkins University in Baltimore, was designed for patients receiving a graft from a donor mismatched at one haplotype, so called haploidentical donor (HAPLO). In the past decade, PTCY has been widely used in HAPLO transplants worldwide, confirming the amazing efficacy of PTCY in preventing GvHD in mismatched grafts.

Recent findings: More recently, PTCY is being tested also in grafts from human leukocyte antigen (HLA) identical related or unrelated donors. In the present review we will also answer several open questions, such as: PTCY and cardiac toxicity; PTCY dose; PTCY timing; PTCY and antithymocyte globulin (ATG); engraftment kinetics; infections; PTCY and leukemia relapse; PTCY and HLA identical grafts.

Summary: PTCY is currently one of the most effective measures to prevent GvHD, and can be customized in different transplant platforms, together with other immunosuppressive agents. There is place for improvement, and several possible modifications of PTCY dose and schedule can be tested in prospective trials.

Purpose of review: DDX41 mutations are the most common cause of germline predisposition to adult-onset myeloid neoplasms. The unique mutational landscape and clinical features indicate a distinct molecular pathogenesis, but the precise mechanism by which DDX41 mutations cause disease is poorly understood, owing to the multitude of DDX41 functions. In this review, we will update DDX41's known functions, present unique clinical features and treatment considerations, and summarize the current understanding of the molecular pathogenesis of the disease.

Recent findings: Large cohort studies have revealed that germline DDX41 variants are heterozygous and predominantly loss-of-function. Acquired mutation of the contralateral DDX41 allele, typically R525H, is present in more than half of patients at disease onset, which occurs after age 50. DDX41 is essential for hematopoiesis and has versatile functions in RNA metabolism and innate immune sensing. Experimental models have suggested that innate immune activation downstream of defects in R-loop resolution and ribosome biogenesis plays a key role in the pathogenesis.

Summary: While intensive investigations unveiled a strong genotype-phenotype relationship, the optimal therapeutic approach and long-term outcome are undefined. There is an urgent need to scrutinize the patients at single cell and multiomics level and to advance experimental animal and human models to fully elucidate the molecular pathogenesis.

Purpose of review: The lack of optimal treatments for haematological disorders has led to the need for prediction models for diagnosis, therapeutic decision-making and life planning. In this review, the worrying current state of predictive models in the field is discussed.

Recent findings: Here, we reviewed 100 studies on prediction models in this field. Our analysis revealed a concerning state of affairs, with a prevalence of suboptimal research methodologies and questionable statistical practices. This includes insufficient sample sizes, inadequate model evaluations, lack of necessary reports of model results, etc. In this regard, we present statistical considerations in the development and validation process of numerous models. This will provide the reader with the statistical knowledge related to prediction model necessary to assess bias in studies, compare other published models and determine the clinical utility of models.

Summary: Awareness among authors, reviewers and editors of the required statistical considerations is crucial. Reinforcing these in all studies involving prediction models is needed. We all should encourage their use in evaluating existing studies and taking them fully into account in future studies.

Purpose of review: This review aims to summarize the histological differences among thrombi in acute myocardial infarction, ischemic stroke, venous thromboembolism, and amniotic fluid embolism, a newly identified thrombosis.

Recent findings: Acute coronary thrombi have a small size, are enriched in platelets and fibrin, and show the presence of fibrin and von Willebrand factor, but not collagen, at plaque rupture sites. Symptomatic deep vein thrombi are large and exhibit various phases of time-dependent histological changes. Cancer-associated venous thromboemboli contain invasive cancer cells that penetrate the vascular walls, and small cancer cell aggregates are observed within the thrombi. The thrombus composition in atherosclerotic and cardioembolic ischemic strokes varies from case to case, while the thrombi in cancer-associated ischemic stroke are rich in platelets and fibrin. A pathological study on amniotic fluid embolism identified uterine vein thrombi and massive platelet-rich microthrombi in the lungs.

Summary: Atherothrombus formation is induced by plaque disruption and may occlude a narrow lumen within a short time. Venous thrombi may grow to a large size in a multistage or chronic manner. Cancer cells can directly contribute to venous thrombus formation. The thrombus formation in amniotic fluid embolism may explain the occurrence of consumptive coagulopathy and cardiopulmonary collapse.

Purpose of review: Despite being discovered decades ago, metastasis remains a formidable challenge in cancer treatment. During the intermediate phase of metastasis, tumor cells detach from primary tumor or metastatic sites and travel through the bloodstream and lymphatic system to distant tissues. These tumor cells in the circulation are known as circulating tumor cells (CTCs), and a higher number of CTCs has been linked to poor prognoses in various cancers. The blood is an inhospitable environment for any foreign cells, including CTCs, as they face numerous challenges, such as the shear stress within blood vessels and their interactions with blood and immune cells. However, the exact mechanisms by which CTCs survive the hostile conditions of the bloodstream remain enigmatic. Platelets have been studied for their interactions with tumor cells, promoting their survival, growth, and metastasis. This review explores the latest clinical methods for enumerating CTCs, recent findings on platelet-CTC crosstalk, and current research on antiplatelet therapy as a potential strategy to inhibit metastasis, offering new therapeutic insights.

Recent findings: Laboratory and clinical data have provided insights into the role of platelets in promoting CTC survival, while clinical advancements in CTC enumeration offer improved prognostic tools.

Summary: CTCs play a critical role in metastasis, and their interactions with platelets aid their survival in the hostile environment of the bloodstream. Understanding this crosstalk offers insights into potential therapeutic strategies, including antiplatelet therapy, to inhibit metastasis and improve cancer treatment outcomes.

Purpose of review: Many epidemiological studies have evidenced an increased bleeding risk associated with selective serotonin reuptake inhibitors (SSRIs), yet the underlying mechanisms remain unclear. This review summarizes data on SSRIs' effects on platelet functions assessed with assays used in clinical practice and highlights the areas that deserve further investigation.

Recent findings: Conflicting results of SSRI effects on platelet aggregation were observed irrespectively of the agonist used, the antidepressant drug or the study type. Alike, discrepant results were reported with flow-cytometry-based assays assessing either platelet surface glycoprotein levels, integrin activation, agonist-induced secretion of intraplatelet granule content or membrane anionic phospholipid exposure. Other tests may have detected a platelet function defect in SSRIs samples, however, results were largely inconsistent.

Summary: Critical literature examination unveils very low certainty of evidence on potential SSRI effect on platelet functions. Findings are often inconsistent even when similar methods are used, most likely because of differences in study design, included patients (age, comorbid conditions), SSRIs' type and dose, uncontrolled confounding factors, and statistical analysis power. Further studies are needed to disentangle any intrinsic antiplatelet effect of SSRIs and the multiple confounding factors, mainly the depression control itself and the degree of platelet SERT inhibition.